The objective of this proposal is a study of some of the pharmacological, biochemical, and physiological parameters involved in histamine receptor(s) (H1 and H2) activity in cardiac and smooth muscle. It will include receptor binding studies, their kinetics, pharmacology, and an attempt to isolate and purify the receptors. The methods will include studies of mechanical responses using isolated spontaneously beating atria (chronotropic activity), electrically driven left atria, ventricular strips and/or papillary muscle (to determine inotropic responses unmodified by chronotropic changes) and isolated smooth muscle from guinea pig and rabbit (aorta and taenia coli). These tissues will be studied using various receptor agonists and antagonists in normal conditions and with altered osmolality, temperatures, etc. Calcium may be involved in agonist and antagonist binding to the histamine receptors and it is probably involved in changes of rate and force resulting from receptor activation. These relationships will be studied using 45Ca ions and various agents which alter calcium permeability. Some animals will be adapted to relative hypoxia (simulated high altitude) and the isolated cardiac muscle will be studied for endogenous histamine content and receptor activity. Radioligand studies of the histamine receptor binding have been initiated and it will be used to determine the kinetics of receptor(s) activity and its modification by various agents. It is essental that a good method be available to characterize and identify the receptors after they are isolated and purified. This will be attempted using affinity chromatography techniques.